lecture 19: sympathetic nervous system drugs Flashcards
noradrenaline (also called norepinephrine)
- neurotransmitter of the sympathetic system
- active even when the individual is at rest
adrenaline (also called epinephrine)
- hormone released from the adrenal gland in response to sympathetic activation
physiological effects of adrenaline/NA
sympathetic activation
–> fight or flight
- increases heart rate
- inhibits secretion
- increases sweating
- inhibits GI motility
- bronchodilation
- vasodilation (muscle, liver, brain)
- vasoconstriction (skin and GIT)
- enhanced neuronal activity
overview of a1 impacts
vasoconstriction (skin and GI)
overview of a2 impacts
modulate sympathetic activity and cognition, arousal, wakefulness (brain)
overview of B1 impacts
- increase HR and force of contraction (heart)
overview of B2 impacts
- vasodilation (increases lung capacity)
- bronchodilation
- gluconeogenesis
adrenergic def
refers to anything related to the neurotransmitters adrenaline and noradrenaline
a1 adrenergic receptos role
–> a1 mediates smooth muscle contraction in the skin
- Gq coupled GPCR
= increases Ca2+ = contraction
- vasoconstriction
= skin and GIT
Agonist: phenylephrine, adrenaline, noradrenaline
- nasal decongest
= vasoconstriction of vessels in the nose
adrenaline effects in the heart
–> B1 activation activates PKA
- PKA phosphorylates troponin 1
= speeds up dissociation of calcium from myofilaments
- PKA also phosphorylates phospholamban (PLB)
= speeds up uptake of Ca2+ into SR
= allows heart to beat faster with stronger force of contraction
where is noradrenaline released from in the brain and how often is it released
–> noradrenaline is released from the locus coerulus (LC)
- higher activity during the day
- LC activity is very low during sleep
- higher activity during stress
noradrenaline several key roles in the brain
- increases arousal
- enhances processing of sensory inputs
- enhances attention
- enhances formation and retrieval of both long term and working memory
- promotes wakefulness
- low levels of NA in the prefrontal cortex (PFC) is indicative of ADHD)
what is attention deficit hyperactivity disorder (ADHD)
- predominantly inattentive subtype
- predominantly hyperactive-impulsive subtype
- a combined subtype
- 6% of children have ADHD
- 2.5% of adults
- 16% of adults may have impairing ADHD symptoms
- 2 fold increased risk of mortality
- low levels of noradrenaline and dopamine in the pre frontal cortex (PFC) contribute to ADHD
how do A1 and A2 receptors influence cognition
–> a2 receptor activation enhances the strength of relevant sensory inout to the PFC
- moderate levels of noradrenaline increase cognition by binding to a2 receptors in the brain
- high levels of noradrenaline also bind to a1 receptors, decreasing cognition
–> nonpharmacological interventions
a2 receptors = inhibitory, inhibits unnecessary info into the cortex, which allows us to focus on only important signals
what are the 4 main ways drugs act to treat ADHD
- inhibit reuptake of noradrenaline and dopamine (methylphenidate)
- inhibit reuptake of noradrenaline only (atomoxetine)
- facilitate the release of noradrenaline and dopamine (amphetamine)
- a2 noradrenaline receptor agonists (guanfacine)
how does a2 increase cognition
- activation of a2 receptors in the brain enhances signal to noise ration of relevant stimuli
- activation hyperpolarises neurons due to Gi coupled GPCR signalling
- decreases neurotransmission of irrelevant stimuli (noise)
how does D1 impact neurotransmission
–> D1 receptor activation enhances neurotransmission of relevant stimuli
–> some studies have found D1 activation increases neurotransmission of delay cell in the prefrontal cortex
- delay cells hold sensory info between a sensory stimulus and subsequent action
- increased delay cell neurotransmission can contribute to improvements in working memory
–> drugs that increase dopamine neurotransmission are called stimulants = increase wakefulness and movement
non-pharmacological treatments for ADHD
–> exercise in children
- improved inattention (effect size =0.92)
- inhibitory control (stroop test effect size = 0.82)
- cognitive flexibility (effect size = 0.52)
- no effect on hyperactivity and behaviour function
–> cognitive-behavioural therapy (CBT)
- CBT in combination with placebo reduced ADHD RS-Inv scale by 10 points compared to 14 points for amphetamine
NET and DAT reuptake inhibitors (NDRIs)
norepinephrine transporter (NET) and dopamine transporter (DAT) remove NA/DA from synapse
- inhibition of NET increases NA in the synapse and binding to a2 receptors
- inhibition of dopamine transporter increases dopamine bindind to D1 receptors
- require natural NA/DA release to work
–> if there is no release of NA in the synapse, there is nothing to activate the receptors
–> lower abuse potential
what is the most prescribed drug for ADHD
methylphenidate
mechanism of a selective NET inhibitor
–> Atomoxetine
- inhibition of NET to increase NA binding to a2 receptors
- inhibition of NET also leads to increased dopamine in the PFC
= limited dopamine transporters in the PFC, so dopamine can share NET transporters
- requires endogenous NA release to work
= if there is no release of NA in the synapse, there is nothing to activate the receptors
= low abuse potential
a2 agonists
- a2 receptor activation by agonists can directly enhance some aspects of cognition
- drugs include guanfacine, clonidine
- presynaptic a2 receptors found in the locus coerulus inhibit the release of noradrenaline
how does amphetamine work
–> amphetamine binds to reuptake transporters in addition to vesicle storage proteins
- causes dopamine and NA to release into the cytoplasm
- dopamine/NA is then transported into the synapse
–> amphetamine increases activtiy even without activation of the LC
–> can exhibit a range of abuse potentials
- intranasal delivery exhibits a high abuse potential
- oral delivery exhibits a low-moderate abuse potential
–> lisdexamfetamine
- prodrug for amphetamine that must undergo metabolism in the liver
= reduces abuse potential
ADHD treatment efficacy
–> meta analysis looking at 113 clinical trials and 14,000 patients found
effect sizes of:
atomoxetine = .39-.51
stimulants = .39-.61
- amphetamine and methylphenidate did not differ in efficacy
–> ADHD medications had no significant effects on broader outcomes like quality of life
